Supraphysiologic extracellular pressure inhibits intestinal epithelial wound healing independently of luminal nutrient flow.
BACKGROUND
Luminal pressure may injure the gut mucosa in obstruction, ileus, or inflammatory bowel disease.


METHODS
We formed Roux-en-Y anastomoses in 19 mice, creating proximal and defunctionalized partially obstructed limbs and a distal limb to vary luminal pressure and flow. We induced mucosal ulcers by serosal acetic acid, and assessed proliferation (proliferating cell nuclear antigen) and ERK (immunoblotting). Parallel studies compared Caco-2 enterocyte migration and proliferation after pressure and/or ERK blockade.


RESULTS
At 3 days, anastomoses were probe-patent, proximal and distal limbs contained chyme, and defunctionalized limbs were empty. The proximal and defunctionalized limbs showed increased pressure and slower healing despite increased proliferation, ERK protein, and ERK activation. In vitro, pressure decreased Caco-2 migration across collagen or fibronectin, stimulated proliferation, and activated ERK. However, ERK blockade did not prevent pressure effects.


CONCLUSIONS
Luminal pressure during obstruction or ileus may impair mucosal healing independently of luminal flow despite increased mitosis and ERK activation.
Flanigan
Thomas L
TL
Departments of Surgery, Anatomy and Cell Biology, John D. Dingell VA Medical Center and Wayne State University, Surgical Service (11S), 4646 John R. St., Detroit, MI 48201, USA.
Owen
Cheri R
CR
Gayer
Christopher
C
Basson
Marc D
MD
D019342:Acetic Acid; D000713:Anastomosis, Roux-en-Y; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D048053:Mitogen-Activated Protein Kinase 6 / Q000096:biosynthesis*; D008938:Mitosis / Q000502:physiology; D011312:Pressure; D014945:Wound Healing / Q000502:physiology*
D005419:Flavonoids; C474633:Mapk6 protein, mouse; D048053:Mitogen-Activated Protein Kinase 6; D019342:Acetic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004121:Dimethyl Sulfoxide